T cells in HCV/HIV co-infection

HCV/HIV 共感染中的 T 细胞

基本信息

批准号：
10318958
负责人：
GEORG Michael LAUER
金额：
$ 64.85万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318958
关键词：
Acute Hepatitis Acute Hepatitis C Aftercare Antiviral Agents Antiviral Therapy Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Chronic Hepatitis C Clinical Data Disease Progression Drug abuse Drug usage Flow Cytometry Generations Genetic Transcription Goals HIV HIV Infections HIV Seropositivity Hepatitis C Hepatitis C Therapy Hepatitis C Vaccine Hepatitis C virus Immune response Immunologics Impairment Individual Infection Injecting drug user Interferons Intervention Laboratories Lead Liver diseases Molecular Outcome Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons Phenotype Population Prevention approach Primary Infection Recovery Risk Role Sampling Substance abuse problem T cell response T-Lymphocyte Testing Transcriptional Regulation United States Virus acute infection anti-hepatitis C base chronic infection co-infection cohort exhaust exhaustion health care availability high risk high risk population injection drug use insight men who have sex with men prevent prophylactic response substance abuser substance use transcriptome sequencing treatment response vaccination strategy

项目摘要

Hepatitis C virus (HCV) remains an urgent global threat, with increasing rates of new infections in many jurisdictions due to a resurgence of injection drug use. People who inject drugs (PWID) and MSM are also at risk for HIV infection and when co-infected with these two viruses they suffer from accelerated liver disease progression and lower treatment response rates when interferon-based therapies were used. New interferon- sparing therapies with direct-acting antivirals (DAAs) lead to cure rates of over 95%, even in HCV/HIV coinfected persons. However, there remains an urgent need to protect high-risk populations from chronic HCV infection and re-infection as treatment alone might be insufficient in these populations with often limited access to health care. Prophylactic interventions will require a better understanding of the immune response necessary for protection from chronic infection and how cured subjects can be prevented from re-infection, with special considerations of additional challenges in the context of HIV co-infection and substance use. In this proposal we focus on the impact of HIV co-infection and of drug abuse on the generation and recovery of HCV- specific T cells during primary infection and after therapy. We will utilize PBMC from well-defined cohorts of persons with acute and chronic HCV/HIV co-infection, including longitudinal samples from patients undergoing DAA therapy, together with direct ex-vivo analysis of HCV-specific CD4 and CD8 T cells by flow cytometry and RNAseq of sorted cells on the single cell and population level. Specifically we will define the impact of HIV co-infection on the quality of the critical CD4 T cell response generated during primary HCV infection in HIV positive hosts, will identify the mechanism enabling sustained and functional HCV-specific CD4 responses in patients receiving early DAA treatment, and will determine whether HIV co-infection and substance abuse impair the recovery of HCV-specific T cells after DAA therapy for chronic HCV infection. The results will deliver important insights into the pathogenesis of HCV infection and will inform immunological approaches for the prevention of chronic HCV infection and re-infection in high risk patients with HIV co-infection and/or substance use.

丙型肝炎病毒 (HCV) 仍然是一个紧迫的全球威胁，许多国家的新感染率不断上升由于注射毒品使用的复苏而导致的司法管辖区。注射吸毒者 (PWID) 和 MSM 也属于感染艾滋病毒的风险，当同时感染这两种病毒时，他们会加速患上肝病当使用基于干扰素的疗法时，进展和较低的治疗反应率。新干扰素- 使用直接作用抗病毒药物 (DAA) 进行节省治疗，即使是 HCV/HIV 患者的治愈率也超过 95% 共同感染者。然而，仍然迫切需要保护高危人群免受慢性丙肝病毒感染感染和再次感染，因为在这些人群中，仅靠治疗可能是不够的，而且接触机会往往有限到医疗保健。预防性干预需要更好地了解免疫反应对于预防慢性感染以及如何防止治愈的受试者再次感染是必要的，特别考虑艾滋病毒合并感染和药物使用方面的其他挑战。在这个该提案我们重点关注艾滋病毒合并感染和药物滥用对丙型肝炎病毒产生和恢复的影响- 原发感染期间和治疗后的特异性 T 细胞。我们将利用来自明确的急性和慢性 HCV/HIV 双重感染人群的 PBMC，包括接受 DAA 治疗的患者的纵向样本，以及直接离体分析通过流式细胞术和 RNAseq 对单细胞和分选细胞进行 HCV 特异性 CD4 和 CD8 T 细胞分析人口水平。具体来说，我们将定义 HIV 合并感染对关键 CD4 T 质量的影响 HIV阳性宿主原发性HCV感染期间产生的细胞反应将确定其机制在接受早期 DAA 治疗的患者中实现持续且功能性的 HCV 特异性 CD4 反应，以及将确定 HIV 合并感染和药物滥用是否会损害 HCV 特异性 T 细胞的恢复 DAA 治疗慢性 HCV 感染。研究结果将为丙型肝炎病毒的发病机制提供重要的见解感染，并将为预防慢性 HCV 感染和再感染的免疫学方法提供信息 HIV 合并感染和/或药物滥用的高危患者。